The interferon-gamma (IFN-y) signature from baseline tumor material predicts pathologic response after neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma.
Authors: Irene L.M. Reijers, Petros Dimitriadis, Elisa A. Rozeman, Oscar Krijgsman, Sten Cornelissen, Linda J.W. Bosch, Annegien Broeks, Alexander M. Menzies, Bart A. van de Wiel, Richard A. Scolyer, Georgina V. Long, Christian U. Blank
Journal: Journal of Clinical Oncology (2022)

9539 Background: Neoadjuvant IPI + NIVO induces high pathologic response rates (pRR) of 74-78% in macroscopic stage III melanoma. Pathologic response ( &lt; 50% viable tumor) is strongly associated with improved relapse-free survival (RFS); the previous OpACIN-neo study demonstrated a 2-year RFS of 96.9% in patients (pts) with pathologic response, whereas the 2-year RFS in non-responders was 35.5%. These data highlight the need for baseline biomarkers predictive for response and survival. Here, we present the predictive value of the 10-gene IFN-y expression signature algorithm (based on Ayers et al.) for pathologic response and relapse in a cohort of melanoma pts treated with neoadjuvant IPI + NIVO. Methods: Baseline tumor biopsies from lymph node metastases of stage III melanoma pts were used for IFN-y signature assessment. Pts were treated with a maximum of two cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg in the OpACIN-neo (arm B) and PRADO studies. RNA expression analysis was conducted using the nCounter® PanCancer Immune Profiling panel on the NanoString Flex machine (NanoString Technologies), which is clinically applicable due to its fast turn-around-time (two days). An IFN-y signature gene expression score (IFN-y score) was calculated using a NKI-developed algorithm. Association between IFN-y score and pathologic response or event-free survival (EFS) was examined by logistic regression and Cox analyses. The optimal cutoff between a high and low IFN-y score was defined based on a summary receiver operating characteristic (sROC) curve. Results: In total, 103 pts treated in the OpACIN-neo and PRADO studies had baseline tumor material available. Median age was 56 years, 62% was male, and 52% had a high baseline IFN-y score. The pRR of the total cohort was 70% (72/103 pts), including 56% (58/103) major pathologic response (MPR, 0-≤10% viable tumor) and 14% (14/103) partial responses (pPR, 10-≤50% viable tumor). 30% (31/103 pts) had no pathologic response. After a median follow-up of 25.2 months, 26 pts (25.2%) developed a melanoma relapse. The IFN-y score was significantly associated with response (OR 1.061, p &lt; 0.001) and relapse (OR 0. 974, p = 0.029). The pRR was 89% (48/54) in pts with a high IFN-y score versus 49% (24/49) in those with a low IFN-y score (p &lt; 0.001). Pts with a high IFN-y score were also less likely to develop a relapse (11% [6/54] versus 41% [20/49], p = 0.001). Conclusions: Pts with a high IFN-y score in pre-treatment biopsies are more likely to respond to neoadjuvant IPI + NIVO with favorable EFS. A rapid gene expression analysis enables the IFN-y score to be used in daily clinical practice to identify pts who might qualify for treatment escalation or de-escalation. The DONIMI study [NCT04133948] currently investigates different neoadjuvant treatment combinations in stage III melanoma pts based on their intratumoral IFN-y score.